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Cell death discovery
Dec 12, 2023;9 (1): 450.

Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.

Yang-Yang Lu, Chun-Yang Zhu, Yi-Xin Ding, Bing Wang, Shu-Fen Zhao, Jing Lv, Shu-Ming Chen, Sha-Sha Wang, Yan Wang, Rui Wang, Wen-Sheng Qiu, Wei-Wei Qi
Author Information
  1. Yang-Yang Lu: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  2. Chun-Yang Zhu: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  3. Yi-Xin Ding: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  4. Bing Wang: Biomedical Centre, Qingdao University, Qingdao, China.
  5. Shu-Fen Zhao: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  6. Jing Lv: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  7. Shu-Ming Chen: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  8. Sha-Sha Wang: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  9. Yan Wang: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  10. Rui Wang: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  11. Wen-Sheng Qiu: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. wsqiuqd@163.com. ORCID
  12. Wei-Wei Qi: Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. qwwqdfy@126.com. ORCID
PMID: 38086844 DOI: 10.1038/s41420-023-01752-z

Abstract

Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

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